I think that COVID-19 was "the end of the road" for fludarabine, cyclophosphamide, and rituximab (FCR) in the United States. At the height of the pandemic, nobody wanted to use a highly myelosuppressive and immunosuppressive chemoimmunotherapy. However, FCR remains noteworthy for its progression-free survival (PFS) plateau. With perhaps the longest follow-up of any CLL clinical trial, Thompson et al showed that FCR can produce a cure fraction, albeit limited to the IGHV-mutated, TP53-nonmutated population. At a median follow-up of 12.8 years, PFS was 53.9% among patients in the subset with the mutated IGHV gene.

COVID-19 aside, frontline CLL treatment today still varies somewhat according to the treatment setting. Clinicians in the community use BTK inhibitors almost exclusively. At academic centers, BTK inhibitors are frequently used, but venetoclax plus obinutuzumab is also a commonly used regimen. The venetoclax ramp-up and monitoring for tumor lysis syndrome is cumbersome in private practice, which is clearly related to this trend. BTK inhibitors are generally the preferred frontline treatment for patients with TP53-aberrant CLL regardless of the setting. 

Acalabrutinib is currently the BTK inhibitor that is the most frequently recommended by those in academic medical centers. This could change in the future because another second-generation BTK inhibitor, zanubrutinib, was recently approved by the US Food and Drug Administration (FDA) for the treatment of CLL. Like acalabrutinib, zanubrutinib has a more favorable cardiovascular risk profile than the BTK inhibitor ibrutinib. Acalabrutinib has also demonstrated excellent efficacy in patients with TP53 aberrancy in a very large cohort of patients with high-risk CLL; however, the duration of follow-up with zanubrutinib is shorter than that of the other BTK inhibitors. Thus, we do not yet have the data to make the bold statement that patients with TP53-aberrant CLL will do just as well with zanubrutinib (eg, out to 4 years).

Ibrutinib plus venetoclax in the front line is another fairly recent development. I think that there had been a lot of excitement in the research community about the potential for fixed-duration ibrutinib plus venetoclax, based on the data from the phase 2 CAPTIVATE trial (NCT02910583), but there are no plans to file an application with the FDA, so we will not have ibrutinib plus venetoclax here.

As Dr O’Brien noted, the FCR regimen is curative in a subset of patients with newly diagnosed CLL. Our group and others have added ibrutinib to FCR, with favorable results, building on Thompson et al's work. These findings are quite compelling for younger patients with CLL, but I agree that the current trend in the United States is moving away from chemoimmunotherapy, and I have not used FCR in several years. FCR is used in first-line settings in other parts of the world, but it has fallen out of favor in the United States.

In the frontline setting, the treatment landscape in the community is dominated by continuous BTK inhibition. The most recent data that I have seen suggested that ibrutinib was still widely used but that acalabrutinib was being used with increased frequency, especially for new starts. I hope that the frontline CLL treatment paradigm continues to evolve away from ibrutinib and toward acalabrutinib and zanubrutinib, based on the head-to-head data showing that both of these drugs are safer than ibrutinib. Regarding the addition of obinutuzumab to BTK inhibitor therapy, I like the idea of adding obinutuzumab if I am concerned that a patient may need a more rapid response. And the acalabrutinib-plus-obinutuzumab data do look quite good. 

I also hope that there will be more evolution toward using venetoclax plus obinutuzumab in the community. We use venetoclax frequently, and, although it creates more work in terms of dose escalation and tumor lysis syndrome monitoring, you can achieve a very long PFS while the patient is off therapy, which may help to avoid the development of resistance. Work is ongoing to develop alternatives to venetoclax that might be a little easier to use in clinical practice, but this does remain a problem.

When people get to the point of needing treatment, we consider factors such as their age, functional status, comorbidities, and CLL genetics, and this largely remains true regardless of recent shifts in the paradigm. In terms of the choice of BTK inhibitor(s), I do not think that anyone is currently initiating therapy with ibrutinib for CLL. I have not written a prescription for ibrutinib for CLL in recent times, perhaps outside of a clinical trial. Second-generation BTK inhibitors are really moving along and are essentially taking the place of the first-generation molecules.

COVID-19 has become endemic and, for most of us, it is now much like the flu and other viral upper respiratory tract infections; however, for patients with CLL, it still can be life threatening. As noted, we saw continued movement away from FCR, in part because it is very myelosuppressive and immunosuppressive. Venetoclax plus obinutuzumab also causes myelosuppression and immunosuppression, and I think of venetoclax as more like a chemotherapy drug. Further, in patients receiving venetoclax, BAX-mutated clonal hematopoiesis arising independently of prior fludarabine-alkylator combination therapy has been observed. I do not use venetoclax plus obinutuzumab in the upfront setting unless a patient has a mechanical valve and needs to be on warfarin or really is just emphatic that they want fixed-duration therapy. 

With the currently available options and other therapies in clinical trials for the relapsed/refractory setting, such as novel noncovalent BTK inhibitors and cellular therapies, progress continues toward the goal of normalizing life expectancy for patients with CLL. Optimizing frontline treatment is an important part of this effort.